Background: Three-dimensional (3D) MR elastography (MRE) derives viscoelastic parameters that may reflect inflammation, but their frequency dependence and the influence of steatosis on inflammation grading and fibrosis staging remain unclear.

Purpose: To investigate 3D multifrequency MRE for assessing hepatic inflammation, fibrosis stage across frequencies, and the influence of steatosis.

Study Type: Prospective.

Population: Sixty-four (40 men, median age: 58 years) participants with chronic liver disease (CLD); 21 (8 men, median age:28 years) healthy volunteers.

Field Strength/Sequence: 3-T; gradient-echo sequence with mechanical vibrations at low (16.7 and 18 Hz), medium (33.4 and 36 Hz), and high (50.1 and 54 Hz) frequencies.

Assessment: In CLD participants, MRE-derived viscoelastic parameters, shear stiffness, storage modulus, loss modulus, and damping ratio were compared with histologically assessed fibrosis, inflammation, and steatosis. MRE test–retest repeatability over 10 min was evaluated in healthy volunteers.

Statistical Tests: Wilcoxon rank sum test, Spearman's correlation, multivariable regression analysis, and area under the receiver operating curve (AUROC). A p value of < 0.05 was considered statistically significant.

Results: Inflammation was significantly independently associated with damping ratio at medium frequency, which showed moderate performance for grading inflammation (AUROC = 0.76–0.83, sensitivity = 0.83–0.84, specificity = 0.70–0.79). Fibrosis staging using shear stiffness and moduli showed high diagnostic performance (AUROC = 0.82–0.95), with comparable accuracy between medium and high frequencies (p = 0.327–0.896). Steatosis was not significantly correlated with MRE overall (p = 0.212–0.459), but was significantly associated with 19% higher stiffness and 20% higher loss modulus at medium frequency in CLD participants without fibrosis or inflammation.

Data Conclusion: Medium frequency 3D MRE demonstrated an independent association with inflammation while preserving accurate fibrosis assessment. Steatosis seemed not to confound MRE-based evaluation.

Level of Evidence: 1.

Technical Efficacy: Stage 2.

Plain Language Summary: Chronic liver disease can cause both inflammation and scarring (fibrosis). Accurate assessment usually requires a biopsy, which is invasive. This study evaluated a noninvasive imaging method called three-dimensional magnetic resonance elastography (3D MRE) in patients who underwent same-day liver biopsy. The researchers tested whether different vibration frequencies could detect inflammation and fibrosis. They found that medium frequency measurements were associated with liver inflammation while still accurately identifying fibrosis. Fat accumulation in the liver did not significantly affect the results. These findings suggest that 3D MRE may help medical doctors assess liver inflammation and fibrosis noninvasively in a single examination.

Objective: Primary sclerosing cholangitis (PSC) is a rare broin ammatory hepatobiliary disease with a highly variable clinical course. Identifying patients at risk for poor outcomes remains challenging. Magnetic resonance imaging (MRI)-based approaches such as DiStrict, Anali score, and relative enhancement (RE) show promise but are limited by operator dependency or static measurements. This study explored pharmacokinetic modelling of liver function as a quantitative imaging biomarker for risk assessment in PSC.

Materials and methods: A prospective cohort of 26 PSC patients underwent up to ve annual MRI examinations with follow-up up to 7.5 years. Clinical endpoints included liver transplantation, decompensated cirrhosis, and cholangiocarcinoma. Correlation and receiver operating characteristics (ROC) analyses compared the pharmacokinetic model with Anali scores, RE, model for end-stage liver disease (MELD), and the Amsterdam–Oxford Model (AOM).

Results: The pharmacokinetic model (ksingle) correlated signi cantly with MELD (r = -0.429, p= 0.029), AOM (r = -0.557, p= 0.003), and endpoint events (r = -0.605, p= 0.001). ROC analysis showed excellent discrimination for ki,single (area under the curve [AUC]= 0.943) outperformed Anali scores (AUC= 0.800–0.829) and comparable to MELD (AUC= 0.857) and AOM (AUC= 0.900).

Conclusion: Pharmacokinetic liver function modelling correlated strongly with MELD and AOM, effectively identifying high-risk PSC patients.

Relevance statement: Pharmacokinetic liver function modelling detects functional impairment in PSC, correlating well with established tools such as the AOM. As an objective, quantitative imaging biomarker, this method may complement established risk scores and aid in the identi cation of patients at risk of adverse outcomes.

Key Points:

● Pharmacokinetic modelling estimates changes in liver function based on MRI.

● These estimates can be used as a prognostic tool in PSC.

● The model’s prognostic performance was comparable to established clinical tests.

Objective: In non-alcoholic fatty liver disease (NAFLD), liver fibrosis is the strongest predictor of adverse outcomes. We sought to investigate the relationship between liver fibrosis and cardiac remodeling in participants from the general population using magnetic resonance imaging (MRI), as well as explore potential mechanistic pathways by analyzing circulating cardiovascular biomarkers.

Methods: In this cross-sectional study, we prospectively included participants with type 2 diabetes and individually matched controls from the SCAPIS (Swedish CArdioPulmonary bioImage Study) cohort in Linköping, Sweden. Between November 2017 and July 2018, participants underwent MRI at 1.5 Tesla for quantification of liver proton density fat fraction (spectroscopy), liver fibrosis (stiffness from elastography), left ventricular (LV) structure and function, as well as myocardial native T1 mapping. We analyzed 278 circulating cardiovascular biomarkers using a Bayesian statistica lapproach.

Results: In total, 92 participants were enrolled (mean age 59.5 ± 4.6 years, 32 women). The mean liver stiffness was 2.1 ± 0.4 kPa. 53 participants displayed hepatic steatosis. LV concentricity increased across quartiles of liver stiffness. Neither liver fat nor liver stiffness displayed any relationships to myocardial tissue characteristics (native T1). In a regression analysis, liver stiffness was related to increased LV concentricity. This association was independent of diabetes and liver fat (Beta = 0.26, p = 0.0053), but was attenuated (Beta = 0.17, p = 0.077) when also adjusting for circulating levels of interleukin-1 receptor type 2.

Conclusion: MRI reveals that liver fibrosis is associated to structural LV remodeling, in terms of increased concentricity, in participants from the general population. This relationship could involve the interleukin-1 signaling.

BACKGROUND: Drug induced liver injury (DILI) is a major concern when developing new drugs. A promising biomarker for DILI is the hepatic uptake rate of the contrast agent gadoxetate. This rate can be estimated using a novel approach combining magnetic resonance imaging and mathematical modeling. However, previous work has used different mathematical models to describe liver function in humans or rats, and no comparative study has assessed which model is most optimal to use, or focused on possible translatability between the two species.

AIMS: Our aim was therefore to do a comparison and assessment of models for DILI biomarker assessment, and to develop a conceptual basis for a translational framework between the species.

METHODS AND RESULTS: We first established which of the available pharmacokinetic models to use by identifying the most simple and identifiable model that can describe data from both human and rats. We then developed an extension of this model for how to estimate the effects of a hepatotoxic drug in rats. Finally, we illustrated how such a framework could be useful for drug dosage selection, and how it potentially can be applied in personalized treatments designed to avoid DILI.

CONCLUSION: Our analysis provides clear guidelines of which mathematical model to use for model-based assessment of biomarkers for liver function, and it also suggests a hypothetical path to a translational framework for DILI.

Background: Different regional depots of fat have distinct metabolic properties and may relate differently to adverse cardiac remodeling. We sought to quantify regional depots of body fat and to investigate their relationship to cardiac structure and function in Type 2 Diabetes (T2D) and controls.

Methods: From the SCAPIS cohort in Linköping, Sweden, we recruited 92 subjects (35% female, mean age 59.5 ± 4.6 years): 46 with T2D and 46 matched controls. In addition to the core SCAPIS data collection, participants underwent a comprehensive magnetic resonance imaging examination at 1.5 T for assessment of left ventricular (LV) structure and function (end-diastolic volume, mass, concentricity, ejection fraction), as well as regional body composition (liver proton density fat fraction, visceral adipose tissue, abdominal subcutaneous adipose tissue, thigh muscle fat infiltration, fat tissue-free thigh muscle volume and epicardial adipose tissue).

Results: Compared to the control group, the T2D group had increased: visceral adipose tissue volume index (P < 0.001), liver fat percentage (P < 0.001), thigh muscle fat infiltration percentage (P = 0.02), LV concentricity (P < 0.001) and LV E/e'-ratio (P < 0.001). In a multiple linear regression analysis, a negative association between liver fat percentage and LV mass (St Beta -0.23, P < 0.05) as well as LV end-diastolic volume (St Beta -0.27, P < 0.05) was found. Epicardial adipose tissue volume and abdominal subcutaneous adipose tissue volume index were the only parameters of fat associated with LV diastolic dysfunction (E/e'-ratio) (St Beta 0.24, P < 0.05; St Beta 0.34, P < 0.01, respectively). In a multivariate logistic regression analysis, only visceral adipose tissue volume index was significantly associated with T2D, with an odds ratio for T2D of 3.01 (95% CI 1.28-7.05, P < 0.05) per L/m² increase in visceral adipose tissue volume.

Conclusions: Ectopic fat is predominantly associated with cardiac remodeling, independently of type 2 diabetes. Intriguingly, liver fat appears to be related to LV structure independently of VAT, while epicardial fat is linked to impaired LV diastolic function. Visceral fat is associated with T2D independently of liver fat and abdominal subcutaneous adipose tissue.

BACKGROUND AND AIMS: Accurate biomarkers for quantifying liver fibrosis are important for clinical practice and trial end-points. We compared the diagnostic performance of magnetic resonance imaging (MRI), including gadoxetate-enhanced MRI and 31P-MR spectroscopy, with fibrosis stage and serum fibrosis algorithms in a clinical setting. Also, in a subset of patients, MR- and transient elastography (MRE and TE) was evaluated when available.

METHODS: Patients were recruited prospectively if they were scheduled to undergo liver biopsy on a clinical indication due to elevated liver enzyme levels without decompensated cirrhosis. Within a month of the clinical work-up, an MR-examination and liver needle biopsy were performed on the same day. Based on late-phase gadoxetate-enhanced MRI, a mathematical model calculated hepatobiliary function (relating to OATP1 and MRP2). The hepatocyte gadoxetate uptake rate (KHep) and the normalised liver-to-spleen contrast ratio (LSC_N10) were also calculated. Nine serum fibrosis algorithms were investigated (GUCI, King's Score, APRI, FIB-4, Lok-Index, NIKEI, NASH-CRN regression score, Forns' score, and NAFLD-fibrosis score).

RESULTS: The diagnostic performance (AUROC) for identification of significant fibrosis (F2-4) was 0.78, 0.80, 0.69, and 0.78 for MRE, TE, LSC_N10, and GUCI, respectively. For the identification of advanced fibrosis (F3-4), the AUROCs were 0.93, 0.84, 0.81, and 0.82 respectively.

CONCLUSION: MRE and TE were superior for non-invasive identification of significant fibrosis. Serum fibrosis algorithms developed for specific liver diseases are applicable in this cohort of diverse liver diseases aetiologies. Gadoxetate-MRI was sufficiently sensitive to detect the low function losses associated with fibrosis. None was able to efficiently distinguish between stages within the low fibrosis stages.Lay summaryExcessive accumulation of scar tissue, fibrosis, in the liver is an important aspect in chronic liver disease. To replace the invasive needle biopsy, we have explored non-invasive methods to assess liver fibrosis. In our study we found that elastographic methods, which assess the mechanical properties of the liver, are superior in assessing fibrosis in a clinical setting. Of interest from a clinical trial point-of-view, none of the tested methods was sufficiently accurate to distinguish between adjacent moderate fibrosis stages.

There is a large and unmet need for diagnostic tool that can be used to characterize chronic liver diseases (CLD). In the earlier stages of CLD, much of the diagnostics involves performing biopsies, which are evaluated by a histopathologist for the presence of e.g. fat, iron, inflammation, and fibrosis. Performing biopsies, however, have two downsides: i) biopsies are invasive and carries a small but non-negligible risk for serious complications, ii) biopsies only represents a tiny portion of the liver and are thus prone to sampling error. Moreover, in the later stages of CLD, when the disease has progressed far enough, the ability of the liver to perform its basic function will be compromised. In this stage, there is a need for better methods for accurately measuring liver function. Additionally, measures of liver function can also be used when developing new drugs, as biomarkers for drug-induced liver injury (DILI), which is a serious drug-safety issue.

Magnetic resonance imaging (MRI) is a non-invasive medical imaging modality, which have shown much promise with regards to characterizing liver disease in all of the abovementioned aspects. The aim of this PhD project was to develop and validate MR-based methods that can be used to non-invasively characterize liver disease.

Paper I investigated if R2* mapping, a MR-method for measuring liver iron content, can be confounded by liver fat. The results show fat does affect R2*. The conclusion was therefore that fat must be taken into account when measuring small amounts of liver iron, as a small increase in R2* could be due to either small amounts of iron or large amounts of fat.

Paper II examined whether T1 mapping, which is another MR-method, can be used for staging liver fibrosis. The results of previous research have been mixed; some studies have been very promising, whereas other studies have been less promising. Unfortunately, the results in Paper II belongs to the less promising studies.

Paper III focused on measuring liver function by dynamic contrast-enhanced MRI (DCEMRI) using a liver specific contrast agent, which is taken up the hepatocytes and excreted to the bile. The purpose of the paper was to extend and validate a method for estimating uptake and efflux rates of the contrast agent. The method had previously only been applied in health volunteers. Paper II showed that the method can be applied to CLD patients and that the uptake of the contrast agent is lower in patients with advanced fibrosis.

Paper IV also used studied liver function with DCE-MRI in patients with primary sclerosing cholangitis (PSC). PSC is a CLD where the bile ducts are attacked by the immune system. When diagnosing PSC patients, it is common to use magnetic resonance cholangiopancreatography (MRCP), which is a method for imaging the bile ducts. Paper IV examined if there was any correlation between number and severity of the morphological changes, seen on MRCP, and measures of liver function derived using DCE-MRI. However, the results showed no such correlation. The conclusion was that the results indicates that MRCP should not be used to predict parenchymal function.

Paper V developed a method for translating DCE-MRI liver function parameters from rats to humans. This translation could be of value when developing new drugs, as a tool for predicting which drugs might cause drug-induced liver injury.

In summary, this thesis has shown that multimodal quantitative MR has a bright future for characterizing liver disease from a range of different aspects.

Purpose: Aiming for non-invasive diagnostic tools to decrease the need for biopsy in diffuse liver disease and to quantitatively describe liver function, we applied a mechanistic pharmacokinetic modelling analysis of liver MRI with Gd-EOB-DTPA. This modelling method yields physiologically relevant parameters and was compared to previously developed methods in a patient group with diffuse liver disease. Materials and Methods: Using data from healthy volunteers undergoing liver MRI, an identifiable mechanistic model was developed, based on compartments described by ordinary differential equations and kinetic expressions, and validated with independent data including Gd-EOB-DTPA concentration measurements in blood samples. Patients (n=37) with diffuse liver disease underwent liver biopsy and MRI with Gd-EOB-DTPA. The model was used to derive pharmacokinetic parameters which were then compared with other quantitative estimates in their ability to separate mild from severe liver fibrosis. Results: The estimations produced by the mechanistic model allowed better separation between mild and severe fibrosis than previously described methods for quantifying hepatic Gd-EOB-DTPA uptake. Conclusions: With a mechanistic pharmacokinetic modelling approach, the estimation of liver uptake function and its diagnostic information can be improved compared to current methods.